Studies on EPEC and EHEC pathogenesis are limited by an extremely complex genome comprising 1387 gains and 528 losses compared to E. coli K12 (for EHEC), and by a lack of functional assays for many of the proposed virulence factors. We have identified a means by which we can study EPEC and EHEC pathogenesis in the nematode C. elegans: under specific growth conditions, the bacteria paralyze and kill the worms. To our knowledge, ours is the only genetic system available for studying EPEC or EHEC pathogenesis. Because both organisms can be genetically manipulated, this system offers the capacity to identify and characterize mutants in both host and pathogen. Models of bacterial pathogenesis in C. elegans have yielded novel mutants in both bacteria and worms that have relevance to pathogenesis in mammalian systems. Here we propose to (i) identify EPEC genes responsible for effects on C. elegans, and test their effects in mammalian pathogenesis; (ii) Identify and characterize genes associated with aging in the worm which confer susceptibility to EPEC; and (iii) identify novel susceptibility genes in C. elegans. It is our expectation that these studies on EPEC and EHEC pathogenesis in C. elegans will permit identification of novel bacterial virulence factors and targets of such factors in nematode and mammalian hosts.